Control of Klebsiella capsule biosynthesis and attachment

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SUMMARY Capsular polysaccharide (CPS) is the outermost barrier between bacteria and their environment. It shapes bacterial interactions with external factors, including adherence to surfaces (e.g. biofilm formation, epithelial cell association); protection from environmental stressors (e.g., dehydration, UV irradiation); susceptibility to predation (e.g., phage, bacteria, or amoeba); or immune evasion (e.g. opsonophagocytosis). The Klebsiella species complex is comprised of non-fastidious Gram-negative bacteria that colonize diverse environments, including soil, sewage, sink drains, and mammalian guts. Klebsiella are early colonizers of the human gastrointestinal tract and, when environmental conditions shift in the gut, they have the potential to bloom and out-compete all other colonizers, including closely related Enterobacterales such as E. coli. Clearly, Klebsiella metabolic capacity is robust and flexible. Moreover, Klebsiella CPS production is required for efficient gut colonization and persistence. There is a major gap in our understanding of how exogenous signals are transduced through Klebsiella metabolism and intracellular regulatory networks to control CPS production and how that CPS is attached to the outer envelope. Our long-term goal is to understand how bacterial control of CPS biosynthesis and attachment shapes fitness in response to changing environmental pressures at both single cell and population levels. The objective of this application is to establish a model of the exogenous and endogenous factors that control Klebsiella CPS biosynthesis and cell surface attachment. We seek to establish a framework for understanding how Klebsiella and other Gram- negative bacteria integrate exogenous nutrient signals with their metabolic and regulatory networks to hone their fitness under varying environmental pressures. Recent progress in the laboratory has identified specific genes and some environmental signals that alter CPS attachment and abundance. Our proposed project areas are to examine (1) the mechanisms controlling CPS attachment and release at the outer membrane and (2) how external nutrient sources and cellular metabolism regulate CPS biosynthesis. The overall vision of our research program is to develop a model of how extracellular signals combined with genetic and regulatory heterogeneity create dynamic surface exposed glycans within a bacterial population to enhance overall fitness in the face of environmental challenges. This will provide the foundation for identifying potential intervention points that could be targeted to modulate bacterial CPS production and decolonize specific niches.